The Journal of Parenteral Science and Technology, Vol. 40, No. 2, 1986, pp. 70-72, describes a method of increasing solubility of anti-infective drugs enoxacin (a naphthyridine) and norfloxacin (a quinoline) by means of salt formation. The four salts found to be best were the aspartate, galacturonate, gluconate, and glutamate.
German application 3635062 covers metal salts of 1-cyclopropylquinoline carboxylic acids used as antibacterials.
European application 191,451 covers 1-cyclopropyl-5-substituted pyrrolidinyl-dihydro-oxonaphthyridines useful as antibacterials with good water solubility.
U.S. Pat. No. 4,359,578 covers the compound enoxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3- carboxylic acid), methods of preparation, and the use thereof as an antibacterial agent. The patent is incorporated herein by reference.
U.S. Pat. No. 4,795,751 covers the compound 5-amino-1-cyclopropyl-6,8-difluoro-7-(3,5-methyl-1-piperazinyl)-1,4-dihydr o-4-oxoquinoline-3-carboxylic acid (Compound A) methods of preparation, and the use thereof as an antibacterial agent. The patent is incorporated herein by reference.
U.S. Pat. No. 4,771,054 covers the compound 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o xo-3-quinoline carboxylic acid, its preparation and use as an antibacterial. The patent is incorporated herein by reference.
U.S. Pat. No. 4,851,418 covers the compound [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)amino]-1-pyrrolidinyl]-1-cyclopropy l-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, its preparation and use as an antibacterial. The patent is incorporated herein by reference.
As a parenteral form, most quinolones and naphthyridines are used in the form of salts which provide acidic parenteral solutions. These formulations are associated with tissue irritation following injection, possibly because of the low pH of the solution.
For parenteral administration, calcium salts are relatively nontoxic compared to other divalent and trivalent salts (e.g., Zn, Mg, Al). The latter salts can cause extreme systemic toxicity. Other di- and trivalent salts besides calcium may be useful for oral formulations of quinolones/naphthyridines.
Concurrent administration of antacids has been implicated as a cause in the decrease in bioavailability of quinolones (Package Insert Cipro.RTM. Tablets: Miles, Inc. Pharmaceutical Division; 400 Morgan Lane; West Haven, Conn. 06516).
Salts frequently contained in the antacids are calcium carbonate, magnesium hydroxide, and aluminum hydroxide. Interaction between quinolones, chiefly nalidixic acid, and metal ions have been reported. (Nakano, Masahiro; Yamamoto, Masakazu; and Arita, Takaichi; "Interactions of Aluminum, Magnesium, and Calcium Ions with Nalidixic Acid," Chem. Pharm. Bull., 26 1505 (1978); Behrens, Barba Norah; and Diaz Guillermo Mendoza; "Metal Complexes of the Antibiotic Nalidixic Acid", Inorganica Chimica Acta, 125 21 (1986); and Vincent, W. R.; Schulman, S. G.; Midgley, J. M., van Oort, W. J.; and Sorel, R. H. A.; "Prototropic and Metal Complexation Equilibria of Nalidixic Acid in the Physiological pH Region" International Journal of Pharmaceutics, 9 191 (1981).
Japanese Application 63-188626 discloses aluminum, zinc, and magnesium compounds for solubilizing amphoteric pyridine carboxylic acids or their salts. These metals have been reported to be toxic, especially when administered parenterally. The reference mentions the addition of sodium, potassium, and calcium chloride to pyridine carboxylic acids. It does not disclose the preparation of sodium, calcium and potassium salts of pyridine carboxylic acid.